Prostate Cancer's Aggressiveness May Be Predicted Early
By the Ratio of Free to Total PSA

The ratio of free to total prostate specific antigen (PSA) in a man's blood may predict at the time of diagnosis whether prostate cancer will be an aggressive, fast-growing disease or a non-aggressive, slow-growing type of cancer. This discovery by researchers at the National Institute on Aging (NIA) and colleagues at the Johns Hopkins University School of Medicine is published in the March, 1997, journal, Urology.

"The ability to differentiate between an aggressive and non-aggressive form of prostate cancer when the disease is diagnosed early puts the physician and patient in a better position to make decisions about treatment," says Dr. E. Jeffrey Metter, Medical Officer for the Baltimore Longitudinal Study of Aging (BLSA) of the NIA, one of the study's authors. "Physicians need a reliable way of distinguishing which cancers are serious, life-threatening tumors and which ones are not. The ratio of free to total PSA in sera may give physicians this information."

Today, physicians have effective means of diagnosing prostate cancer, but there is great debate about which treatment is best for a cancer diagnosed in the early stage-watchful waiting, surgery to remove a localized cancer, or radiation therapy. Each has advantages and disadvantages. Radiation and surgery may be associated, in some cases, with complications including impotence and incontinence. Watchful waiting means living with cancer and possibly missing an opportunity for cure.

"This preliminary study suggests that the free to total PSA ratio may be valuable to the physician at the time of cancer diagnosis to help in the choice of management since the more aggressive cancers need to be treated," says Metter.

PSA, an enzyme produced by the prostate gland, is found in high concentration in semen where it acts to liquefy the seminal fluid after ejaculation so that sperm can swim freely. Some PSA leaks into the blood stream from prostatic cells, more so in the presence of prostate disease such as infection, enlargement called benign prostatic hyperplasia (BPH) or cancer. Part of the PSA binds proteins in the blood and some PSA remains free or unbound. Free and bound PSA make up total PSA in serum.

Men whose total PSA levels are high may have an infection, prostate enlargement, or cancer. Earlier studies have found that the rate of increase in total PSA levels over time is one of the best predictors of whether prostate cancer is present or not. This study suggests that in men who are diagnosed with prostate cancer, the ratio of free to total PSA is an early indicator of the degree of aggressiveness of the cancer.

The NIA and Hopkins team measured free and total PSA levels on stored, frozen sera from men who are participants in the BLSA, a longitudinal study of aging that was established in 1958. The stored blood samples were available up to 15 years before diagnoses for 20 men, 12 with aggressive and eight with non-aggressive cancers. Since these cancers were detected late-in an era before PSA was available-the researchers could more accurately separate aggressive and non-aggressive cancers by combining the cancer stage and the appearance of the cancer under the microscope.

At a time when total PSA levels were not different between those with aggressive cancer and those with non-aggressive cancer (10 years before diagnosis), there was a statistically significant difference in the ratio of free to total PSA between men with aggressive and men with non-aggressive cancers (p=0.008). Among 14 men who had sera available for analysis at 10 years before diagnosis, all eight with aggressive cancers had a free to total PSA ratio of 0.14 or less, whereas only two of six men, or 33 percent, with non-aggressive cancer had a ratio of 0.14 or less at 10 years before diagnosis. In other words, having a larger fraction of the total PSA protein-bound appears to predict for more aggressive cancer. If these results are confiremed prospectively in a larger group of patients, it may be possible to use the free-to-total PSA ratio to determine which men require early therapeutic intervention and which may be safely observed without early therapy.

"These data are very preliminary and further studies will be needed before this finding can be used in clinical practice," says Dr. H. Ballentine Carter, a urologist at Johns Hopkins School of Medicine who worked on the study. Dr. Metter adds, "The next step is to conduct studies of a larger sample of men with prostate cancer to see if these findings are repeated."

"Screening for prostate cancer using the PSA test is still controversial," says Carter. "However, the rate of detection of advanced, non-curable disease has markedly diminished among populations with high rates of screening, and the National Cancer Institute (NCI) has recently reported decreases in prostate cancer deaths in the U.S."

To help address the cancer screening controversy, the NCI has launched a large study to determine whether screening tests for prostate, lung, colorectal and ovarian cancers will reduce the number of deaths from these cancers. The Prostate, Lung, Colorectal & Ovarian Cancer Screening Trial (PLCO) will involve 150,000 Americans nationwide, 55 but not yet 75 years of age. Half of the people will receive screening tests and the other half will not. Both groups will complete a questionnaire about their health every year for up to 14 years. For more information, or to apply for the study, contact the NCI at 1-800-4-CANCER.

In 1997, an estimated 334,500 new cases of prostate cancer will be diagnosed, and prostate cancer will be responsible for an estimated 41,800 deaths. Prostate cancer rates are 37 percent higher for black men than white men. Between 1980 and 1990 prostate cancer incidence rates increased 65 percent, largely due to improved detection.